Film coating

ABSTRACT

A film coating composition suitable for use in coating pharmaceutical formulations comprising a) an acrylic polymer dispersion, e.g. an ethylacrylate/methylmethacrylate copolymer such as Eudragit NE30D, b) a surfactant, c) sodium stearyl fumarate, and d) a water-containing liquid useful for the achievement of controlled release from pharmaceutical formulations such as tablets, pellets, etc.

This application is a 371 of PCT/SE02/000103, filed Jan. 22, 2002.

FIELD OF THE INVENTION

The present invention relates to a new film coating. More specificallythe present invention relates to a new film coating for the achievementof controlled release from pharmaceutical formulations such as tablets,pellets, etc. wherein the film coating may be applied in a substantiallyaqueous environment. Furthermore, the invention provides a process forthe preparation of such a film coating.

BACKGROUND OF THE INVENTION

Oral administration of a drug is the most convenient for the patient.Proper formulations must also meet the requirements of safety andsimplicity. Depending on the properties of a drug and the therapeuticrequirements different approaches must be taken during the formulationwork to obtain the required delivery profile of the drug. Thus,sparingly soluble drugs to be given once a day require other types offormulations than easily soluble drugs to be taken several times a day.The matter has been discussed extensively in the literature andcomprehensive reviews can be found, e g Langer and Wise (Eds) “Medicalapplications of controlled release”, vols I and II, CRC Press Inc, BocaRaton, 1984; Robinson and Lee (Eds) “Controlled drugdelivery—fundamentals and applications”, Marcel Dekker, NY 1987;Bogeritoft and Sjögren, in “Towards better safety of drugs andpharmaceutical products” (Ed: Braimer), Elsevier, 1980; Sandberg“Extended-release metoprolol”, Thesis, Uppsala University, 1994.

Different formulations have different mechanisms controlling the releaseof the active substance. In the thesis by Sandberg 1994,extended-release (ER) formulations of different types of drugs arereviewed. It is concluded that in principle two types of ER dosage formsexist; the matrix system where the drug is mixed with the matrixmaterial (often a polymer or a wax); and the drug reservoir system wherethe drug is formulated into a core (tablet or pellets) surrounded by apolymeric film. The film is then a release rate-controlling barrierdetermined by, e g its dissolution rate, its permeability, thesolubility of the substance, etc.

From a flexibility point of view the formulation of a drug into smalldiscrete units coated with a film has gained much attention. Suchformulations show several interesting features, e g flexibility indosage and modification of release properties, different dosage formscan be developed, dose size is adaptable to suit fixed combinations,tablets can be made divisible etc. In a number of studies it was shownthat safe, simple, and convenient therapy could be achieved utilisingthis principle for the drug metoprolol and its salts (Ragnarsson et al,Drug Develop Ind Pharmacy 13, 1495 (1987); Sandberg et al, Eur J ClinPharmacol 33, S3 (1988) and S9 (1988); Ragnarsson et al, Int JPharmaceutics 79, 223 (1992); Sandberg et al, Ibid 68, 167 (1991);Sandberg et al, Pharmaceuticl Res 10, 28 (1993); Sandberg et al, DrugInvest 6, 320 (1993); Sandberg, Thesis Uppsala University, 1994).

The formulation of metoprolol into pellets according to the abovementioned references utilised a film coating sprayed from a solution ofethyl cellulose and hydroxypropyl methyl cellulose in an organicsolvent. However, for environmental reasons it will be necessary in thenear future to utilise water based film forming systems for this andother drugs to be formulated as pellet systems. Also, tablet coatings ingeneral utilising organic solvents must for the same reasons beexchanged with water based film forming materials. Thus, much effort hasbeen directed to find suitable water based systems for film coatings indrug delivery systems.

Latex particles in water as the dispersion medium have been known foralmost half a century. These particles are polymeric colloidal particlesin the 10 to 1000 nm range and have been utilised as film formers, e gin paints, in floor coatings, printing inks, adhesives etc. If theparticle polymer has a sufficiently low glass transition temperature(Tg) when the water is evaporated, the particles can coalesce to form afilm.

Water based film-forming polymer latexes for the pharmaceutical industryhave been known since the early eighties when commercial dispersionsmore frequently appeared on the market (e g Aquacoat, FMC Corp.;Eudragit E-30D, Röhm Pharma). Further development has given severalother products that have been tested and reported in a number ofpublications (Petereit and Weisbrod, Eur J Pharmaceutics and Biopharm47, 15 (1999); Petereit et al, Ibid, 41, 219 (1995); Amighi and Moës,STP Pharma Sci 7, 141 (1997); Bodmeier and Paeratukul, Pharm Res 11, 882(1994); Ozturk et al, J Controlled Release 14, 203 (1990). Goodhart etal, Pharmaceutical Tech April, 64 (1984); Bodmeier and Paeratakul Int JPharmceutics 152, 17 (1997); Bodmeier and Paeratakul Drug Develop IndPharmacy 20, 1517 (1994)).

From these and other studies it can be concluded that one of the moreinteresting dispersions, due to the low Tg of the latex polymer, isEudragit® NE30D, which contains approximately 28.5% w/w particles of thecopolymer poly(ethylacrylate—co-methylmethacrylate), and 1.5% w/w of thenon-ionic tenside Nonoxynol 100 (a polyoxyethylated nonylphenol) as thestabiliser. However, to obtain best spraying conditions and technicalappearance of the film-coated pellets, an anti-sticking agent has to beadded to the dispersion as reported by Petereit and Weisbrod 1995. Onesuch agent is a glyceryl monostearate (GMS). It was also reported,however, that best performance of the dispersion during spraying and ofthe dried film was obtained when the GMS was dispersed with an extrasurface active agent, e g polysorbate 80 (PS80). On the other hand, wehave found that it has been difficult to obtain results with acceptablereproducibility with respect to, e g permeability and release rates fromformulations manufactured according to these suggested procedures. Onetentative explanation for this might be that the properties of theGMS/PS80 dispersion, e g size of dispersed particles, highly depend onprocess parameters like temperature, type of mixing etc, which also canbe concluded from the results in the paper by Petereit and Weisbrod1995.

Anti-sticking agents, also named detackifiers, glidants, and lubricants,are well-known agents used during pharmaceutical work. Similarsubstances have been used as anti-caking agents in food industry. Themost commonly used substances for these purposes are, e g stearates,talc, polyethylene glycols, paraffines, lauryl sulphates, silica, andstarches (M E Aulton (Ed) Pharmaceutics—the science of dosage formdesign Churchill Livingstone 1988; Susan Brewer Food Additives, documentEHE-677 Illinois Co-operative Extension Service, 1994; M Ash and I Ash(Eds) Handbook of Pharmaceutical Additives, Gower Publishing Ltd, 1995).In connection with film-forming dispersions the most popularanti-sticking agents seem to be GMS, talc, and silica. However, in mostof these latter applications reported these substances must first bedispersed with other added material, preferably surfactants oramphiphilic polymers to obtain more homogeneous systems.

Several patents or patent applications utilising these principles exist.Thus, Wolff et al, WO 00/13687; Wolff et al, WO 00/13686; Nagy et al, WO99/42087; Lee et al, WO 99/30685; Eichel et al, U.S. Pat. No. 5,529,790;Eichel U.S. Pat. No. 5,478,573; Chen, U.S. Pat. No. 5,260,068; Petereitet al, EP 403,959; disclose the use of Eudragits for the (controlled)release of different types of drugs. In those applications whenanti-sticking agents have to be used, combinations of surface activemolecules and talc or stearates are most common. However, for ourpurposes these approaches are not attractive since several problems mayarise due to, e g the combination of non-compatible materials, largeamounts of extra dispersion additives, non-reproducibility duringmanufacturing, etc.

Sodium stearyl fumarate (sodium salt of 2-butenedioic monooctadecylester; Pruv™) is a pharmaceutical additive normally used as a lubricantfor tabletting, where it in many cases can substitute and is superiorto, e g magnesium stearate (Handbook of Pharmaceutical Excipients (Eds:A Wade and P J Weller) 2nd edition, Pharmaceutical Press, London 1994; AW Hözer and J Sjögren Int J Pharmaceutics 2, 145 (1979); G K Bolhuis andA W Hölzer in Pharmaceutical powder compaction technology (Eds GAldeborn and C Nyström), Marcel Dekker Inc, NY 1995, chapter 16). Also,Pruv is approved for several food applications (Code of FederalRegulations, title 21, volume 3, part 172). Its solubility in water canbe described by 1 g (solubility (gram Pruv/gram water))=0.057*T/(°C.)−5.7 according to the data given in the Handbook. Thus, at e g 60° C.the solubility is 0.005 gram per gram water. Further, its HLB valuecalculated according to the method by Davies (B Jönsson, B Lindman, KHolmberg, and B Kronberg Surfactants and polymers in aqueous solutionsJohn Wiley & Sons, Chichester, 1998 p 353) amounts to about HLB=19.

PURPOSE OF THE INVENTION

The purpose of the present invention is to provide a new film coatingsystem that does not have the above mentioned problems. Improvedproperties of the new film coating system are, for example,non-stickiness, reproducibility during processing and a minimal additionof extra additives to the dispersion before the film forming process.Another aspect of the invention is to provide a method of manufacturingcoated formulations, for example pellets or tablets, utilising this newfilm forming system.

SUMMARY OF THE INVENTION

We have now surprisingly found a novel film coating composition whichprovides a latex dispersion suitable for coating pharmaceuticalformulations wherein the film produced serves as a barrier giving closeto constant release (zero-order) from the formulation. In addition thephysical properties of the film produced were such that no processingproblems, for example adhesion, were experienced.

The present invention provides a film coating composition suitable foruse in coating pharmaceutical formulations comprising

-   a) an acrylic polymer dispersion-   b) a surfactant-   c) sodium stearyl fumarate and-   d) a water-containing liquid.

DETAILED DESCRIPTION OF THE INVENTION

In another aspect the invention provides a film coat covering apharmaceutical core wherein the core comprises a pharmacologicallyactive ingredient and optionally one or more pharmaceutically acceptableexcipients wherein the film coat comprises

-   a) an acrylic polymer-   b) a surfactant and-   c) sodium stearyl fumarate,    wherein the film coat has been deposited from a water-containing    liquid.

Suitably the film coat has a thickness in the range of 1 to 100micrometers, preferably in the range of 5 to 50 micrometers and morepreferably in the range of 10 to 30 micrometers.

In another aspect the invention provides a pharmaceutical formulationcomprising

-   a) a pharmaceutical core comprising a pharmacologically active    ingredient and optionally one or more pharmaceutically acceptable    excipients and-   b) a film coat comprising-   i) an acrylic polymer-   ii) a surfactant and-   iii) sodium stearyl fumarate,    wherein the film coat has been deposited from a water containing    liquid.

In a preferred aspect of the invention the pharmacologically activeingredient is provided in a plurality of beads optionally containing oneor more pharmaceutically acceptable excipients wherein each of the beadsis coated with a film coat as defined above. Such film coated beads maybe provided in sachets or formulated as a capsule, for example a hardgelatin capsule, or compressed to form tablets using known methods withthe optional addition of other pharmaceutically acceptable additives.Coated beads to be compressed into a tablet are obtained by conventionaltechniques known to those skilled in the art.

Also, during this process suitable other agents can be added. Forexample, during the tabletting step suitable fillers, egmicrocrystalline cellulose, talc. sodium stearyl fumarate etc can beutilised to give acceptable compression characteristics of theformulation, e g hardness of the tablet.

Suitably the beads have a diameter in the range of 0.01-2 mm. preferablyin the range of 0.05-1.0 mm and more preferably in the range of 0.1-0.7mm.

Optionally the beads may contain an insoluble core onto which the activeingredient has been deposited for example by spraying. Suitablematerials for the inert core are silicon dioxide, glass or plastic resinparticles. Suitable types of plastic material are pharmaceuticallyacceptable plastics such as polypropylene or polyethylene preferablypolypropylene. Such insoluble cores have a size diameter in the range of0.01-2 mm, preferably in the range of 0.05-0.5 mm and more preferably inthe range of 0.01-0.3 mm.

In a more preferred aspect the present invention provides a controlledrelease formulation wherein the pharmacologically active ingredient iscontrolled over a long period of time, for example 8 to 24 hourspreferably 20 to 24 hours, in comparison to an immediate release tablet.

Preferably the pharmacologically active ingredient has activity in thetreatment of cardiovascular and gastrointestinal diseases. In particularthe pharmacologically active ingredient is a beta-blocking adrenergicagent. The beta-blocking adrenergic agents referred to in thisapplication include but are not limited to the compounds selected fromthe group consisting of acebutolol, alprenolol, amosulalol, arotinolol,atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopindolol,bucumolol, bufetolol, bufuralol, bunitrolol, buprandolol, butofilolol,carazolol, carteolol, carvedilol, celiprolol, cetamolol, cloranolol,dilevalol, epanolol, indenolol, labetalol, levobunolol, mepindolol,metipranolol, metoprolol, moprolol, nadolol, nadoxolol, nebivalol,nipradilol, oxprenolol, perbutolol, pindolol, practolol, pronethalol,propranolol, sotalol, sufinalol, talindol, tertatolol, tilisolol,timolol, toliprolol, and xibenolol, and stereoisomers thereof andpharmaceutically acceptable salts or solvates thereof, or solvates ofsuch salts. A preferred beta-blocking adrenergic agent is metoprolol ora pharmaceutically acceptable salt thereof.

Alternatively the pharmacologically active ingredient is acholesterol-lowering agent including but not limited to an HMG-CoA(3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitor. The HMG-CoAreductase inhibitor may be a statin selected from atorvastatin,bervastatin, cerivastatin, dalvastatin, fluvastatin, itavastatin,ivastatin, lovastatin, mevastatin, nicostatin, pravastatin, rivastatin,rosuvastatin and simvastatin. Particularly preferred statins are,however, those disclosed in European Patent Application No.EP-A-0114027, or a pharmaceutically acceptable salt, especially sodium,or solvate thereof, or a solvate of such a salt, and a compound with thechemical name(E)-7[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)-amino]-pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid, and salts thereof such as its calcium and sodium salts aredisclosed in European Patent Application, Publication No. EP-A-0521471,and in Bioorganic and Medicinal Chemistry, (1997), 5(2), 437-444.

In the present patent application, the term “cholesterol-lowering agent”includes chemical modifications, such as esters, stereoisomers, prodrugsand metabolites, whether active or inactive, and pharmaceuticallyacceptable salts or solvates of any of these, or solvates of such salts.

The pharmaceutical formulations of the present invention may be used totreat cardiovascular and gastrointestinal diseases.

In yet another aspect the invention provides a controlled releasemetoprolol formulation comprising

a) a metoprolol core comprising metoprolol or a pharmaceuticallyacceptable salt thereof and optionally one or more pharmaceuticallyacceptable excipients and

b) a film coat as defined above.

In a preferred aspect the core comprising metoprolol or apharmaceutically acceptable salt thereof comprises a plurality of beadswhich comprise metoprolol or a pharmaceutically acceptable salt thereofand optionally one or more pharmaceutically acceptable excipientswherein each of the beads is coated with a film-coat as defined above.Preferably the beads have an inert core as described previously.

Suitable pharmaceutically acceptable salts of metoprolol include thetartrate, succinate, fumarate or benzoate salts and especially thesuccinate salt. The S-enantiomer of metoprolol or a salt thereof,particularly the benzoate salt or the sorbate salt, may also be used.

The term acrylic polymer dispersion as used herein means a polymer, orcopolymer comprising two or more, of the following monomers: acrylicacid and esters thereof particularly the methyl, ethyl, propyl and butylesters; and methacrylic acid and esters thereof particularly the methyl,ethyl, propyl and butyl esters, which is dispersed in a substantiallyaqueous liquid preferably water. Also hydroxylated acrylic andmethacrylic esters are included.

In one aspect the present invention provides film coatings which aresuitable for giving extended release. Suitably the acrylic polymerdispersion used in this case comprises homogeneous particles wherein thepolymer or copolymer has a T_(g)<room temperature for example acrylateand/or methacrylates such as a methyl acrylate/methyl methacrylatecopolymer or a butyl acrylate/methyl methacrylate copolymer. One groupof preferred acrylic polymers for this use comprises an ethylacrylate/methyl methacrylate copolymer for example Eudragit® NE30D inwhich the ethyl acrylate concentration is about 67 mol % or an ethylacrylate/methyl methacrylate copolymer copolymer described in theJournal of Applied Polymer Science 1970, 14, 73-78 in which the ethylacrylate concentration is greater than 50 wt %.

Alternatively the acrylic polymer dispersion used to obtain extendedrelease suitably comprises heterogeneous particles comprising a corepolymer or copolymer and a shell polymer or copolymer wherein the shellpolymer or copolymer has a T_(g)<room temperature, for example a butylacrylate polymer, and the core polymer or copolymer has a Tg>roomtemperature. Preferably the shell polymer comprises acrylate and/ormethacrylate polymers or copolymers wherein the Tg is less than roomtemperature. More preferably the shell polymer is an ethyl acrylatepolymer.

In another aspect the present invention provides film coatings which aresuitable for providing an enteric coating. Suitably the acrylic polymerused in this case comprises homogeneous particles wherein the polymer orcopolymer has T_(g)<room temperature in aqueous dispersion but hasT_(g)>room temperature in the dry state. Suitable polymers compriseacrylic acid and esters thereof particularly the methyl, ethyl, propyland butyl esters; and methacrylic acid and esters thereof particularlythe methyl, ethyl, propyl and butyl esters. Particularly preferredpolymers are those provided under the tradenames Eudragit L30D® (RöhmPharma) or Eudragit FS30D® (Röhm Pharma). Optionally furtheranti-tacking agents may be required.

Suitably the amount of the acrylic polymer in the film coatingcomposition is in the range of 15 to 50% by weight. Preferably theamount of the acrylic polymer in the film coating composition is in therange of 20 to 40% by weight. More preferably the amount of the acrylicpolymer in the film coating composition is in the range of 25 to 35% byweight.

Suitably the amount of the acrylic polymer in the film coat is in therange of 80 to 99.5% by weight. Preferably the amount of the acrylicpolymer in the film coat is in the range of 85 to 99% by weight. Morepreferably the amount of the acrylic polymer in the film coat is in therange of 85 to 95% by weight.

Suitably the surfactant is one of the following:

a nonionic surfactant, like sorbitan esters (Span series); polysorbates(Tween series); polyoxyethylated glycol monoethers (like the Brijseries); polyoxyethylated alkyl phenols (like the Triton series or theIgepal series); alkyl glucosides (e g dodecylmaltoside); sugar fattyacid esters (e g sucrose laurate); saponins; etc: or mixtures thereof;ampholytic surfactants, like betaines;anionic surfactants, like sulphated fatty alcohols eg sodiumdodecylsulphate SDS; sulphated polyoxyethylated alcohols; others likedioctyl sulphosuccinate; bile salts (e g dihydroxy bile salts likesodium deoxycholate, trihydroxy bile salts like sodium glycocholate,etc); fusidates (e g sodium dihydrofusidate); etccationic surfactants, like ammonium compounds;soaps, fatty acids, and lipids and their salts, like alkanoic acids; (eg octanoic acid, oleic acid); monoglycerides (eg monolein),phospholipids which are neutral or positively or negatively charged (egdialkyl phosphatidylcholine, dialkyl phosphatidylserine, etc); etc;More preferably the surfactant is a nonionic surfactant. Most preferablythe surfactant is nonoxynol 100.

Suitably the amount of the surfactant in the film coating composition isin the range of 0.05 to 8% by weight. Preferably the amount of thesurfactant in the film coating composition is in the range of 0.1 to 6%by weight. More preferably the amount of the surfactant in the filmcoating composition is in the range of 0.5 to 4% by weight.

Suitably the amount of the surfactant in the film coat is in the rangeof 0.05 to 12% by weight. Preferably the amount of the surfactant in thefilm coat is in the range of 2 to 10% by weight. More preferably theamount of the surfactant in the film coat is in the range of 4 to 8% byweight.

In a most preferred embodiment of the present invention the acrylicpolymer and the surfactant are provided by Eudragit® NE30D incompositions, a film coats or formulations defined previously.

Sodium stearyl fumarate (alternatively known as the sodium salt of2-butenedioic monooctadecyl ester) is available from Penn-WestPharmaceuticals under the tradename PRUV®.

Suitably the amount of the sodium stearyl fumarate in the film coatingcomposition is in the range of 0.05 to 8% by weight. Preferably theamount of sodium stearyl fumarate in the film coating composition is inthe range of 0.1 to 6% by weight. More preferably the amount of sodiumstearyl fumarate in the film coating composition is in the range of 0.5to 4% by weight.

Suitably the amount of sodium stearyl fumarate in the film coat is inthe range of 0.05 to 12% by weight. Preferably the amount of sodiumstearyl fumarate in the film coat is in the range of 2 to 10% by weight.More preferably the amount of sodium stearyl fumarate in the film coatis in the range of 4 to 8% by weight.

Suitably the water-containing liquid comprises water and a watermiscible organic liquid for example lower alkanols e.g. ethanol,propanol or isopropanol. From a safety point of view is preferred thatthe proportion of the organic is kept to a minimum but small amounts aretolerable for example in the range of 0 to 20% by volume. Preferably theliquid is water.

The film-coating composition is particularly suitable for use as anaqueous film-coating composition wherein the film-coat is applied usingwater as the liquid. When the liquid is water the latex is preferably apoly(ethylacrylate-co-methylmethacrylate) copolymer, for exampleEudragit NE30D® (Röhm Pharma). This process is particularly advantageousas it negates the need to use environmentally unacceptable organicsolvents, some of which also present processing problems due to theirinflammablility, while also eliminating many of the problems experiencedwith aqueous coatings described above.

In another aspect the present invention provides processes for thepreparation of the film-coating composition. Therefore there is provideda process for the preparation of a film-coating composition comprisingmixing together the acrylic polymer dispersion, the surfactant, sodiumstearyl fumarate and the liquid at a temperature in the range of 10 to100° C.

In one embodiment of the process the acrylic polymer dispersion, thesurfactant, sodium stearyl fumarate and the liquid are mixed at roomtemperature and then slowly heated, while stirring carefully, to thedesired temperature, preferably about 60° C. After a couple of minutesthe mixture is then slowly cooled, while stirring carefully, to roomtemperature before film preparation by, for example, spraying.

In another embodiment, sodium stearyl fumarate is first mixed with theliquid and slowly heated to the desired temperature, preferably about60° C., while carefully stirring the mixture. After a couple of minutes,the acrylic polymer dispersion and the surfactant are then added, thestirring continued for a couple of minutes, and the mixture cooled asabove.

In yet another embodiment, sodium stearyl fumarate, the acrylic polymerdispersion and the surfactant are first mixed and heated to the desiredtemperature, preferably about 60° C., while stirring carefully. Theliquid, which can be preheated or not, is then added and the mixturethen handled as above.

Other protocols than these typical general approaches are possible.Thus, for example the temperature during the mixing of the components ispreferably about 60° C. However, other temperatures, higher or lower canbe chosen to meet special requirements in different applications. Lowertemperatures will give larger particles of sodium stearyl fumarate inthe mixtures when cooled to room temperature. Higher temperatures can bechosen and are recommended when high contents of sodium stearyl fumarateare required. Also, other additives, e g extra surfactant, colours etccan be added at any time during the process.

Suitably mixing is achieved by methods such as stirring or shaking butother methods of homogenization known to those skilled in the art may beused.

In another aspect the present invention provides a process for filmcoating a pharmaceutical core wherein a film coating composition asdefined above is applied to a core. Preferably the film coatingcomposition is applied by spraying for example in a fluidised bed withtop spray or bottom spray techniques. Other coating methods used arecoating in standard coating pans with perforated pans, Accela-cota,immersion swords, Glatt, or immersion tubes as described in “Theory andPractice in Industrial Pharmacy” edited by Lachman, published by Lea andFeabiger 1986 3^(rd) edition.

In another aspect the invention provides a process to prepare a filmcoat as defined above comprising removing the liquid from a film coatingcomposition as defined above. Suitably the liquid is removed byevaporation for example by spray drying for example in a fluidised bed.When coating the tablets in a standard coating pan, hot air is used fordrying.

In yet another aspect the invention provides a process to prepare aformulation as defined above comprising coating a pharmaceutical core asdefined above with a film coating composition as defined above.

In a further aspect the invention provides a process to prepare aformulation in which the pharmacologically active ingredient is providedas a plurality of beads as defined above comprising coating theplurality of beads with a film-coating composition as defined above.

Typically a film coating composition comprises

a) 25 to 35% by weight of an acrylic polymer dispersion

b) 0.1 to 4% by weight of a surfactant

c) 0.1 to 4% sodium stearyl fumarate and

d) a water-containing liquid to 100%.

EXAMPLES

The following examples are non-limiting and are given by way ofillustration only. It will be appreciated by those skilled in the artthat the examples are to be looked upon as guidelines, and the inventionis not restricted to the exemplified compositions. A wide range ofcombinations is possible to give film coatings having the necessaryproperties required for each specific application.

Example 1 Preparation of Free Films from Sodium Stearyl Fumarate andNE30D®

Three mixtures of sodium stearyl fumarate and NE30D® were prepared atroom temperature accordingly:

A: 10.323 g NE30D®+0.0149 g sodium stearyl fumarate+3.75 ml H₂O (giving0.11% w/w sodium stearyl fumarate, with sodium stearyl fumarate/particleratio approximately 0.5%);

B: 10.278 g NE30D®+0.0304 g sodium stearyl fumarate+3.75 ml H₂O (giving0.22% w/w sodium stearyl fumarate, with sodium stearyl fumarate/particleratio approximately 1%);

C: 10.407 g NE30D®+0.0508 g sodium stearyl fumarate+3.75, ml H₂O (giving0.35% w/w sodium stearyl fumarate, with sodium stearyl fumarate/particleratio approximately 1.6%);

The mixtures were heated slowly to 60° C. while gently stirring. After 2minutes, the dispersion was cooled (no heating) to room temperaturewhile gently stirring. Free films (10×10 cm²) of the three dispersionswere obtained by pouring approximately 10 ml of each dispersion inTeflon moulds, which were set aside at 25° C., 60% relative humidity fordrying and film-formation during 18 hrs.

Results:

The stickiness of the films was tested by simple manual handling of thefilms. The best non-sticky film was judged to have been obtained fromdispersion mixture C. Therefore, this film was tested in a permeabilityexperiment, as described in Example 2.

Comparative Example 1 Preparation of Films from GMS/PS80/NE30D

Three mixtures of GMS, PS80 and NE30D® were prepared. Different mixingconditions of GMS and PS80 were used to examine the influence of thestirring rate. Thus, first GMS and PS80 were mixed according to eitherD, E, or F below. Then, appropriate amounts of this dispersion wereadded to NE30D® to give the intended compositions. The same amounts ofGMS, PS80, and NE30D® were used, namely 0.225 g GMS, 0.090 g PS80, and15.0 g NE30D which gave dispersions with 1.5% w/w GMS (GMS/particleratio=5%). This composition was taken from the paper by Petereit andWeisbrod 1995.

D: 1 hour; homogenizer at 6000 rpm; 65° C.;

E: 20 min; homogenizer at 3000 rpm; 65° C.;

F: 4 hours; magnet stirring; 65° C.

Free films (10×10 cm²) of the three dispersions were obtained by pouringapproximately 10 ml of each dispersion in Teflon moulds, which were setaside at 25° C., 60% relative humidity for drying and film-formationduring 18 hrs.

Example 2 Permeability of Free Films

Pieces of the films C, D, E, and F prepared according to Examples 1(film C) and Comparative Example 1 (films D, E, F) were mounted indiffusion chambers consisting of two chambers separated by a free film(Hjärtstam, Thesis, Chalmers University of Technology, Göteborg 1998).The transport of labelled water was followed from the donor side to thereceiver side over the membrane at 25° C. Appropriate volumes were takenfrom the receiver side at different times. The permeability of a filmwas calculated from the slope of the data of transported amount oflabelled water vs time.

Results:

The results from the permeability experiments are shown in Table 1. Itis seen that highly variable permeability was obtained with the threeGMS/PS80/NE30D dispersions. However, the trend in the data suggestedthat a protocol which produced better dispersed GMS particles gave alower permeability (D better than E better than F). Nevertheless, it wasnot possible to obtain the low permeability shown by Film C obtainedfrom the sodium stearyl fumarate/NE30D dispersion according to thisinvention. Moreover, the permeability of Film C was comparable to whatcould be expected with a free film typical for the organic solvent basedfilm (G) used for coating of the drug metoprolol (Lindstedt, Ragnarsson,and Hjärtstam, Int J Pharmaceutics 56, 261 (1989). Thus, superiorquality of free film could be obtained with the present invention withonly one additive and under very simple processing (gentle stirringduring 2 minutes at 60° C.) before film-preparation.

TABLE 1 Permeability of free films Film C D E F G Permeability (m² s⁻¹ ×10¹²) 1.8 30.1 40.5 51.0 >1.8 (1.8-10)

Example 3 Preparation of Coated Metoprolol Succinate Pellets

Film coating on metoprolol succinate pellets (size fraction 0.40-0.63mm, with inert silicon dioxide cores) was carried out on alaboratory-scale, fluid-bed Wurster apparatus. Two mixtures wereprepared as coating solutions:

A: 0.916 g sodium stearyl fumarate was added to 67.59 g water. 186.62 gof NE30D was then added (giving 0.36% w/w sodium stearyl fumarate, witha sodium stearyl fumarate/particle ratio approximately 1.6% assumingthat NE30D contains 30% particles). The mixture was heated slowly tobetween 57-60° C. while gently stirring. After 2 minutes, the mixturewas allowed to cool (no heating) to room temperature while gentlystirring.B: 1.86 g sodium stearyl fumarate was added to 67.08 g water. 186.31 gof NE30D was then added (giving 0.73% w/w sodium stearyl fumarate, witha sodium stearyl fumarate/particle ratio approximately 3.3% assumingthat NE30D contains 30% particles). The mixture was heated slowly to 61°C. while gently stirring. After 5 minutes, the mixture was allowed tocool (no heating) to room temperature while gently stirring.

The coating conditions were as follows:

Bed weight 200 g Coating solution ~170 g Spraying rate 5.3 g/minAtomising air pressure 2.5 bar Fluidising air flow rate 35 m³/h Inletair temp. 30° C. Outlet air temp. 20° C.

The coating pellets were then dried in the fluid-bed, 40° C. (approx. 20min.). During this step the fluidising air flow rate was kept atapproximately 20 m³/h.

Results: No problems, e g sticking of pellets, were met during theprocess.

Example 4 Release of Metoprolol from Coated Pellets

The release of metoprolol from about 100 mg pellets made according toExample 3 was studied at 37° C. using the USP dissolution apparatus II(rotating paddle) with stirring rate=100 rpm. The release medium wascomposed of phosphate buffer with the ionic strength=0.1 M and thepH=6.8. Samples were withdrawn for analysis (absorbance of metoprolol at273 nm in a 1 cm cell). Amounts of released metoprolol were determinedfrom measurements of the absorbance of a standard metoprolol solutionbased on the same medium as used in the release experiments.

Results: The amounts of released metoprolol vs time are given in Table 2referring to the different coating solutions A and B made according toExample 4. It is seen that a close to constant release of metoprololfrom the coated pellets was obtained during most of the time for bothpreparations after an initial lag time phase. Fastest release wasobserved from pellets coated with a coating solution containing moresodium stearyl fumarate (preparation B). The reason for the low standarddeviation (SD) in the second experiment was attributed to the fact thatthe release studies in this case were carried out with an automaticinstrument set-up.

TABLE 2 Release (%) of metoprolol from coated pellets Time/hrs 0.5 1 2 34 6 8 10 12 16 18 20 (A) % released 0.7 0.6 1 — 4 14 26 37 47 — — 86 SD(%) 0.3 0.5 0.6 1 1 2 2 2 2 (B) % released — 3 4 9 16 29 41 52 63 79 8487 SD (%) 0 0 0 0 0 0 0 0  0  0 0

Example 5 Preparation of Tablets from Coated Metoprolol Pellets

The coated drug pellets A and B made according to Example 3 were mixedwith equal amounts of microcrystalline cellulose, Avicel PH102 in aTurbula mixer T2C (Willy A. Bachofen, Switzerland) for approximately 4minutes. After addition of 0.15% sodium stearyl fumarate the powder masswas mixed for 2 minutes. After the mixing was ended the mass wascompressed to tablets on an excenter press (KilianSP300, Germany) usinga pressure of approx. 8 kN. Typical tablet weights were around 200 mgwith slightly less than 50 mg metoprolol in each tablet.

Result: No problems were met during the tabletting of the coatedpellets.

Example 6 Release of metoprolol from tablets of coated pellets

The release of metoprolol from tablets made according to Example 5 wasstudied at 37° C. using the USP dissolution apparatus II (rotatingpaddle) with stirring rate=100 rpm. The release medium was composed ofphosphate buffer with the ionic strength=0.1 M and the pH=6.8. Sampleswere withdrawn for analysis (absorbance of metoprolol at 273 nm in a 1cm cell). Amounts of released metoprolol were determined frommeasurements of the absorbance of a standard metoprolol solution basedon the same medium as used in the release experiments.

Results:

The amounts of released metoprolol vs time are given in Table 3referring to the different pellets A and B made according to Example 3.It was found that acceptable release profiles were obtained.

TABLE 3 Release (%) of metoprolol from tablets compressed from coatedpellets Time/hrs 0.5 1 2 3 4 6 8 10 12 16 18 20 (A) % 14 19 30 — 44 5564 72 79 — — 102 released SD (%)  2 2 2 3 4 5 4 5 4 (B) % — 12 23 32 4151 60 67 73 83 86 89 released SD (%) 1 2  3 3 4 4 4 5  5  4 5

1. A composition producing an extended-release film coat when applied to a pharmaceutical formulation, wherein the composition comprises an admixture of the following components: a) an ethylacrylate/methylmethacrylate copolymer dispersion, b) a surfactant, c) sodium stearyl fumarate, and d) a water-containing liquid, and wherein the amount of ethylacrylate/methylmethacrylate copolymer in the film coating composition is in the range of 15 to 50% by weight.
 2. The composition as claimed in claim 1, wherein the water-containing liquid is water.
 3. The composition as claimed in claim 1, wherein the surfactant is nonoxynol
 100. 4. The composition according to claim 1, wherein the surfactant is nonoxynol 100 and the water-containing liquid is water.
 5. A process for the preparation of a composition producing an extended-release film coat according to any one of claim 1, 2, 3 or 4, comprising mixing together an ethylacrylate/methylmethacrylate copolymer dispersion, a surfactant, sodium stearyl fumarate and a water-containing liquid at a temperature in the range of 10 to 100° C.
 6. An extended-release film coat covering a pharmaceutical core, wherein the core comprises a pharmacologically active ingredient and optionally one or more pharmaceutically acceptable excipients, wherein the film coat comprises an admixture of the following components: a) an ethylacrylate/methylmethacrylate copolymer, b) a surfactant, and c) sodium stearyl fumarate, and wherein the film coat has been deposited from a water-containing liquid and the amount of the ethylacrylate/methylmethacrylate copolymer in the film coat is in the range of 80 to 99.5% by weight.
 7. The film coat according to claim 6, wherein the surfactant is nonoxynol
 100. 8. The film coat to claim 6, wherein the surfactant is nonoxynol 100 and the water-containing liquid is water.
 9. A process to prepare an extended-release film coat according to any one of claim 6, 7 or 8, comprising the steps: a) mixing together an ethylacrylate/methylmethacrylate copolymer dispersion, a surfactant, sodium stearyl fumarate and a water-containing liquid at a temperature in the range of 10 to 100° C. to produce a film coating composition; b) depositing the film coating composition on the pharmaceutical core; and c) removing the liquid from the film composition.
 10. A pharmaceutical formulation comprising: a) a pharmaceutical core comprising a pharmacologically active ingredient and optionally one or more pharmaceutically acceptable excipients, and b) an extended-release film coat comprising an admixture of the following components: i) an ethylacrylate/methylmethacrylate copolymer, ii) a surfactant, and iii) sodium stearyl fumarate, wherein the film coat has been deposited from a water-containing liquid and the amount of the ethylacrylate/methylmethacrylate copolymer in the film coat is in the range of 80 to 99.5% by weight.
 11. A process to prepare a formulation as claimed in claim 10, comprising the steps: a) mixing together an ethylacrylate/methylmethacrylate copolymer dispersion, a surfactant, sodium stearyl fumarate and a water-containing liquid at a temperature in the range of 10 to 100° C. to produce a film coating composition; b) coating the pharmaceutical core with the film coating composition; and c) removing the liquid from the film forming composition.
 12. A pharmaceutical formulation comprising a pharmacologically active ingredient which is provided in a plurality of beads, wherein the beads optionally contain one or more pharmaceutically acceptable excipients, wherein each bead is coated with an extended-release film coat comprising an admixture of the following components: a) an ethylacrylate/methylmethacrylate copolymer, b) a surfactant, and c) sodium stearyl fumarate, and wherein the film coat has been deposited from a water-containing liquid and the amount of the ethylacrylate/methylmethacrylate copolymer in the film coat is in the range of 80 to 99.5% by weight.
 13. The formulation according to claim 10 or 12, wherein the pharmacologically active ingredient has activity in the treatment of cardiovascular or gastrointestinal diseases.
 14. The formulation according to claim 13, wherein the pharmacologically active ingredient is a beta-blocking adrenergic agent.
 15. The formulation according to claim 14, wherein the pharmacologically active ingredient is metoprolol or a pharmaceutically acceptable salt thereof.
 16. The formulation according to claim 15, wherein the metoprolol salt is the tartrate, succinate, fumarate or benzoate salt.
 17. A process to prepare a formulation as claimed in claim 12, comprising the steps: a) mixing together an ethylacrylate/methylmethacrylate copolymer dispersion, a surfactant, sodium stearyl fumarate and a water-containing liquid at a temperature in the range of 10 to 100° C. to produce a film coating composition; b) coating the plurality of beads with the film coating composition; and c) removing the liquid from the film forming composition.
 18. The formulation according to claim 10 or 12, wherein the surfactant is nonoxynol
 100. 19. The formulation of claim 10 or 12, wherein the surfactant is nonoxynol 100 and the water-containing liquid is water.
 20. The formulation according to claim 10 or 12, wherein the pharmacologically active ingredient has activity in the treatment of cardiovascular or gastrointestinal diseases.
 21. The formulation according to claim 20, wherein the pharmacologically active ingredient is a beta-blocking adrenergic agent.
 22. The formulation according to claim 21, wherein the pharmacologically active ingredient is metoprolol or a pharmaceutically acceptable salt thereof.
 23. The formulation according to claim 22, wherein the metoprolol salt is the tartrate, succinate, fumarate or benzoate salt.
 24. A composition producing an enteric film coat when applied to a pharmaceutical formulation, wherein the composition comprises an admixture of the following components: a) an ethylacrylate/methylmethacrylate copolymer dispersion, b) a surfactant, c) sodium stearyl fumarate, and d) a water-containing liquid, and wherein the amount of ethylacrylate/methylmethacrylate copolymer in the film coating composition is in the range of 15 to 50% by weight.
 25. An enteric film coat covering a pharmaceutical core, wherein the core comprises a pharmacologically active ingredient and optionally one or more pharmaceutically acceptable excipients, wherein the film coat comprises an admixture of the following components: a) an ethylacrylate/methylmethacrylate copolymer, b) a surfactant, and c) sodium stearyl fumarate, and wherein the film coat has been deposited from a water-containing liquid and the amount of the ethylacrylate/methylmethacrylate copolymer in the film coat is in the range of 80 to 99.5% by weight.
 26. The film coat according to claim 6 or 25, wherein the amount of surfactant is in the range of 0.05 to 12% by weight.
 27. The film coat according to claim 6 or 25, wherein the amount of sodium stearyl fumarate is in the range of 0.05 to 12% by weight.
 28. A pharmaceutical formulation comprising: a) a pharmaceutical core comprising a pharmacologically active ingredient and optionally one or more pharmaceutically acceptable excipients, and b) an enteric film coat comprising an admixture of the following components: i) an ethylacrylate/methylmethacrylate copolymer, ii) a surfactant, and iii) sodium stearyl fumarate, wherein the film coat has been deposited from a water-containing liquid and the amount of the ethylacrylate/methylmethacrylate copolymer in the film coat is in the range of 80 to 99.5% by weight.
 29. A pharmaceutical formulation comprising a pharmacologically active ingredient which is provided in a plurality of beads, wherein the beads optionally contain one or more pharmaceutically acceptable excipients, wherein each bead is coated with an enteric film coat comprising an admixture of the following components: a) an ethylacrylate/methylmethacrylate copolymer, b) a surfactant, and c) sodium stearyl fumarate, and wherein the film coat has been deposited from a water-containing liquid and the amount of the ethylacrylate/methylmethacrylate copolymer in the film coat is in the range of 80 to 99.5% by weight. 